Ketamine – Magic Antidepressant, or Expensive Illusion?

By Neuroskeptic | March 7, 2012 8:09 pm

Not one but two new papers have appeared from the Carlos Zarate group at NIMH reporting that a single injection of the drug ketamine has rapid, powerful antidepressant effects.

One placebo-controlled study found a benefit in depressed bipolar patients who were already on mood stabilizers. The other found benefits in treatment-resistant major depression, though ketamine wasn’t compared to placebo that time. Here’s the bipolar trial:

There have now been several studies finding dramatic antidepressant effects of ketamine, a compound that all journalists seem contractually bound to call either a or a “club drug” or a “horse-tranquilizer”. Great news?

If you believe it. But hold your, er, horses… there’s a problem. As I said almost 3 years ago about one of the earlier ketamine trials:

In theory, the trial was double blind – neither the patients nor the doctors knew whether they were getting ketamine or placebo. But you’ll know when you’ve been injected with 0.5mg/kg ketamine. You get high. That’s why people take it [recreationally]. The study can’t really be called double blind.

To their credit, Zarate et al did acknowledge this, and suggested that in future ketamine could be compared to another drug which produces noticeable effects. But they really should have done that to begin with.

It’s now 2012, and there have still not been any published studies comparing ketamine to an active comparator i.e. a different drug that produces noticable psychoactive effects, to avoid unblinding. This means it’s 12 years since the initial pilot report on ketamine in depression, and 6 years since the first large trial appeared.

The authors of the 2006 paper themselves wrote that “limitations in preserving study blind may have biased patient reporting… One potential study design in future studies with ketamine might be to include an active comparator” and suggested amphetamine for the big role.

Good idea. But six years later, we’re still waiting. Which is really a bit silly. There have been dozens of papers written about the possible antidepressant effects of ketamine, from human trials to mouse work. That’s a lot of research dollars (and dead mice) on something that might just be an active placebo.

Looking at the registered ketamine research on clinicaltrials.gov, I found that four active-comparator ketamine trials are in the pipeline (1,2,3,4), plus one cancelled (5). Only one is for depression though. The others being for OCD, cocaine dependence and suicidal ideation.

In all of these trials a benzodiazepine is the active comparator. Is that a good idea? Well, it’s certainly better than nothing, but I wonder.

An active comparator has to “make an impression” on the patient equal to that produced by the real drug.  The null hypothesis, remember, is that ketamine has no specific antidepressant effect. That means it produces improvement through a combination of a) the placebo effect (expectation) and b) non-specific psychoactive changes.

More on that second one: any psychoactive drug might relieve depression by “taking your mind off it” and a change in mental state, as provided by a drug, also provides a demonstration that “I won’t always feel this way”. By showing that states of consciousness are products of brain chemistry, almost any drug could therefore offer a “glimmer of hope” to the depressed. If all this sounds very subjective, it is, but that’s the point. Psychiatry is.

Would a benzo make as big an impression as 0.5 mg/kg ketamine IV? It’s impossible to predict, really; so we’d need to ask people about the subjective strength of the drug effect. Personally, I worry that a lot of people just get sleepy on benzos and don’t really feel much, so I’d prefer they used something a bit more hard-hitting like amphetamine, but maybe that’s just me.

There’s a deeper problem though. Suppose our ketamine-benzo trial finds no difference between ketamine and benzo. A critic could say, ah, but maybe it was just a “failed trial”, so it doesn’t overturn the positive studies. The patients weren’t properly diagnosed, or weren’t depressed enough, or were too depressed, etc.

Nitpicking such differences between studies is a well-practiced art.

Critics could complain in other ways if the study did find a benefit of ketamine. As I see it, the only way to settle this once and for all is to do a three-way randomized controlled trial – inactive placebo vs. active comparator vs. ketamine.

That way, if it’s a failed trial, we’d know: there’d be no difference between ketamine and the inactive placebo. If there was a difference, but the active comparator was just as good as ketamine, that means it was all about nonspecific effets. Finally, if ketamine was better than the other two conditions, we could be pretty confident it was really working.

Also important is the question of volunteer expertise; subjects shouldn’t be able to tell what drug they’re on, but people who’d taken ketamine and/or the comparator drug before might be able to do that, so you’d want naive volunteers.

In conclusion: It’s possible that ketamine has no specific antidepressant effects. To find out we ideally need a three-way trial, with both active and inactive comparators, careful monitoring of subjective drug effects and patient knowledge and expectations. Until that happens, I will be skeptical of ketamine in depression.

This is not because I just think it’s impossible. Ketamine profoundly affects the brain in ways that we don’t understand. I’ve suffered depression and I know it can come and go in a matter of minutes. So I think it’s entirely possible that it works – but it’s also possible that it’s a nonspecific effect.

Look. I really want to know the answer to this. Both as a neuroscientist, and as a depression sufferer, this is very important to me. That’s why we urgently need a good trial.

Link: See also the discussion and the comments over at The Neurocritic and this Scientific American piece which is pretty good except that it doesn’t cover the active placebo issue.

ResearchBlogging.orgZarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, and Luckenbaugh DA (2012). Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biological psychiatry PMID: 22297150

Ibrahim, L., et al. (2012). Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study Neuropsychopharmacology DOI: 10.1038/npp.2011.338

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  • CM

    If the action of ketamine is non-specific and also applies to other drugs with dissociative effects, that doesn't make it an “expensive illusion”. For one, ketamine is cheap compared to most antidepressants, so expensive is way off base. Currently administration costs a little because it is done on a one off basis, but it is intrinsically easier than ECT and it would be easy to set up a protocol to do it on the ward if the evidence base continues to accrue and it gains widespread acceptance.

    Second, even if its action is non-specific, it is still likely to be useful. Your hypothesis could be reframed as saying that other dissociative substances might be equally useful. If ketamine and high dose benzo are found to be equivalent, it doesn't change the fact that ketamine is clearly better than nothing and better than placebo. It would mean that non-specific dissociative effects of psychoactive substances can play an acute role in relieving depression. In cases of acute suicidal depression or where comorbidities (eg psychosis) led to treatment resistance this could be life saving.

    You might call it an “expensive illusion”. I would call your strong language a “dangerous fallacy”. We really don't have many (any) antidepressants or behavioral techniques with a consistent rapid effect. Having one could drastically alter the trajectory of illness for some people. Having a theory about exactly how it works is highly relevant to affective neuroscience but really not the primary clinical concern.

  • http://www.blogger.com/profile/00187465138890222167 LokaSamasta

    Man, have you tried ashtanga yoga sun-salutations? Very good anti-depressant.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    I have used ketamine therapeutically for some of our patients with treatment refractory depression. It has worked wonders in situations where dozens of antidepressants, antipsychotics, mood stablizers, anxiolytics and years of psychotherapy have failed.

    I am convinced from clinical experience that for some patients it is extremely effective. I have been able to avoid hospitalizing patients who entered our office acutely suicidal because the 40 minute ketamine treatment completely eliminated their suicidal ideation immediately. (Btw, avoiding an admission with an hour of my time and $5 of ketamine is extremely cost effective!)

    I have seen no other medication, drug of abuse or placebo that has effects that rapid or as powerful in treatment refractory patients.

    I believe that more research needs to be done, but primarily to determine safety of repeated treatments and determine predictors of response rather than establish efficacy.

    To me, the most problematic issue in the ketamine literature is the use of measures like the HAM-D and MADRS at 6 hours and 24 hours. These rating scales are meant to assess functioning over 1 week, not shorter time periods. It is meaningless to use them in the way that Zarate did.

  • http://www.blogger.com/profile/00827267450019132624 Ken

    NMDA receptors are intimately involved in neurogenesis, and NMDA blockade has been shown to increase neurogenesis in the dentate gyrus (see Cameron et al. 1995).

    Certainly not the only reason ketamine has an antidepressant effect, due to the rapid onset, but I wouldn't be surprised if ketamine induces neurogenesis by antagonizing NMDARs and that contributes to it's antidepressant effect over the long term

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    CM: I agree to some extent, but surely you'd agree that if the effects of ketamine are nonspecific, it would be good to know that, if only because it would point the way to even cheaper & safer nonspecific treatments with the same efficacy.

    Ketamine may be cheap compared to ECT or a long course of treatment, but it's still an IV infusion over 40 minutes; it would be even cheaper if you could, say, give a sublingual benzo and get the same effect.

  • http://www.blogger.com/profile/12975382358013125434 Kay Walker

    I'm here as usual saying that controlled trials are useless for anything other than eliminating contenders with strong negative effects/side effects. Groups of depressed people don't think and feel as a group, their brain chemistry is probably at lots of different stages; people can be susceptible to getting good or bad effects from genetic factors we can and can't measure; trials are never long enough for some people; the dose chosen may have no effect or too great an effect due to metabolic differences. etc et. Try individuals on ketamine if you must, titrating the dose against normal functioning and any side effects and against placebo and alternatives if you want. I don't think any sort of controlled group trials will ever be very useful for assessing the positive side of anti-depressant medications on psychological symptoms. I'm fairly sure the same should apply to any psycho-active substance. Too unpredictable and not enough known about why they produce the effects on brain chemistry that we assume they do.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    Anyone who has worked in the Psych ER will tell you that a sublingual benzo has minimal benefit for mood and suicidal ideation. Any benefit on anxiety is short lived and definitely does not last 1 week as seen with ketamine.

    The leading neurobiological theory for the beneficial effects of ketamine is that it blocks NMDA which leads to diversion of gluamate signalling to AMPA receptors. AMPA receptors induce the mTOR pathway and lead to increased neurogenesis. However, neurogenesis occurs much more slowly than the antidepressant and antianxiety effects are seen clinically. I believe that the acute effects are probably related to direct interruption of signalling between the prefrontal cortex and the limbic system.

  • http://www.blogger.com/profile/09374512270335764119 Maia Szalavitz

    Also, it's important to note that these RCT's aren't the only evidence in favor of ketamine: several studies with ECT using ketamine or different anesthetics show that ketamine, but not the others, enhances the effects of ECT.

    That is definitely a blinded situation, given that the patients are unconscious!!! Not to mention the fact that drugs with similar mechanisms of action seem to also have antidepressant effects.

  • http://www.blogger.com/profile/12987483359214068938 Will:Power

    This comment has been removed by the author.

  • Anonymous

    The ethical aspects of giving severely depressed patients a psychoactive drug like amphetamine are also a big concern. There are both real ethical concerns and real IRB roadblocks for this idea.

  • http://www.blogger.com/profile/12987483359214068938 Will:Power

    Neurosceptic,

    Points taken, but I think you are unnecessarily sceptical. Of course none of what I'm about to say affirms ketamines antidepressant activity in any way, but might just balance the discussion a bit.

    Most trials showing the efficacy of ketamine are on TRD patients who have presumably knowingly already tried other drugs with minimal benefit (including ECT). This might suggest they will be less prone to a dramatic placebo or self-driven response.

    http://www.ncbi.nlm.nih.gov/pubmed/21466832

    I'm also not sure the extent to which ketamine produces marked dissociative effects in these antidepressant trials.

    http://www.ncbi.nlm.nih.gov/pubmed/19897179
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061550/

    Furthermore even if ketamine produced a marked dissociative effect in patients whilst also removing their depression, it is still rapidly removing their depression, which maintains for a week or more afterwards. This suggests it may be dramatically changing the neurobiological correlates underlying depression. It seems unlikely that TRD patients would be capable of achieving this themselves through placebo or experience-based enlightenment, given the very persistent nature of their depression.

    It is also notable that most other conventional monoaminegic drugs may induce side-effects that alert your awareness to their presence in your system way before antidepressant effects appear weeks later. I myself experienced this with all the antidepressants I went on. Most made me feel worse first, and not much better later.

    Zigs,

    Rapid enhancements in synaptogenesis likely underlie the antidepressant effects of NMDAR antagonists. Memantine and CP-101-606 (GluN2B antagonist) demonstrate similar behavioural and neurogenic effects in animals to ketamine.

    Oddly many people believe in neurogenesis based hypotheses of depression yet can't see the obvious connection to the NMDAR. Unlike other receptors the NMDAR is connected to all the pathways currently thought to be involved in the pathophyisiology of depression, i.e. nNOS, PI3K, ERK, GSK3B, CREB, BDNF, VEGF, etc. It is typically activity-dependant NMDAR activation which leads to rapid and long-term changes to neuroplasticity.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    @Anonymous – Ketamine is not a stimulant and does not give a “high” or euphoria in the way that cocaine or heroin does. It produces unusual a dissociative experience that patients describe more as feeling “light”, “stoned” or “floaty”. They also describe that the sense of “heaviness” and severe tension that is associated with depression is reduced or eliminated.

    Also, we have not seen our patients develop cravings for ketamine the way that people crave stimulants, alcohol, opiates and cocaine (although we have not used it in patients with a history of substance dependence).

    @Will:Power – I am not saying that neurogenesis is not involved at all, but that it does not make sense that it is entirely responsible for the rapid initial benefits. I find it hard to believe that synaptogenesis, which would gene transcription can occur within 40 minutes. If you have references supporting this, I would greatly appreciate if you could post them. Thanks.

  • Anonymous

    Zigs

    I was referring to Neuroskeptics idea of using amphetamine as an active placebo.

    Regarding the dissociative state, it may have similarities to a petit mal, ketamine may produce a similar EEG pattern.

    Thus, there may be a common denominator here in ETC and Ketamine

  • http://www.blogger.com/profile/12987483359214068938 Will:Power

    Zigs;

    Rapid enhancement of the mTOR signaling pathway in the PFC is required for ketamine's antidepressant-like effects in animals.

    http://www.ncbi.nlm.nih.gov/pubmed/20724638

    Notably mTOR signaling is decreased in MDD post-mortem.

    http://www.ncbi.nlm.nih.gov/pubmed/21635931

    2 studies have also shown marked decreases in NMDAR subunits in the PFC, whilst one reported a massive increase in the amygdala.

    I do think basic brain inter-regional signalling will also be involved. For instance what enables us to experience good and bad feelings moment to moment throughout the day. You can produce rapid antidepressant-like effects by stimulating the nucleus accumbens in TRD patients. NMDAR antagonists may correct PFC-hippocampal-amygdala-Nac circuitry.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838907/

    Monoaminergic antidepressants can simply be seen to be slowly modulating the glutamate system, which is afterall the core brain signaling system.

    Why is the glutamatergic system going wrong in people with depression and dementia? Research what stress does to it. Open your mind further and see what diet and the rest of the environment does to it.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    @Anonymous – I doubt that it is similar to a seizure as patients are always alert and oriented throughout the treatment. You are able to have a normal conversation with them. That would not be the case for a petit mal or partial complex seizure.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Thanks for the great comments. I will reply to them all eventually.

    Anonymous: Well, speaking as a depressive I would much sooner have had some amphetamine than some ketamine when I was depressed (setting aside the possible antidepressant effects – I mean in terms of psychoactivity).

    Also, they used to give amphetamine to treat depression (still do in very treatment resistant cases I believe) & they still give it to people with ADHD. So… I hope it would pass ethics.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Will:Power – I agree with all those points. They are excellent points. However as you say, they're not knock-down arguments.

    I think this issue is so important that we need knock-down arguments.

    If ketamine is an antidepressant, not just nonspecifically, it has huge direct implications for the clinic but even bigger indirect implications for neuroscience & also for future drug development.

    Certainly I would say that research $s would be much better spent on settling this issue than on testing yet another me-too monoaminergic.

  • http://www.blogger.com/profile/08971958802099534733 Christina

    I'm not a scientist or anything, but I pretend to know things and your conclusion and suggestions seem logical to me. As someone who has suffered from depression and treated it in a variety of ways, I am skeptical of drugs like this. Of course, different things work for different people which is why I think we should try and get as many options as possible. In addition to struggling myself, I also lost a family member to depression, nothing worked for him but I think the field of neuroscience has so many promising angles for helping people who suffered like he did. Keep fighting the good fight. :)

  • Lars

    Isn't there a possible study design you are forgetting? I know that MAPS are using three different dosages of MDMA in their upcoming PTSD trials (though they didn't do so in their past, completed one). The idea of using a psychoactive placebo has also been suggested.

  • http://www.blogger.com/profile/00827267450019132624 Ken

    A few recent studies have pointed to tianeptine's action on NMDA receptors as a possible mechanism of action, and tianeptine (like ketamine) is known for the rapid onset of its antidepressant effects, as well as it (likely indirectly) increasing dopamine concentrations in the forebrain (the NA IIRC). I wonder if there's something there.

    But definitely, Neuroskeptic, I think we should quit banging out new reuptake enhancers every year; even the recent round of SNDRIs has been rather dissapointing.

    As far as I know there hasn't been a concerted, organized push towards glutamatergic antidepressants yet, although there is a lot of evidence that both NMDARs and AMPARs are involved in both neurogenesis and mood regulation.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    @Will:Power – Thanks for the references. The first study that you posted showed that synaptogenesis was evident in rats at 24 hours after ketamine treatment. 24 hours is a time frame that makes sense if gene transcription is involved. However, ketamine reduces dysphoria, suicidal ideation and anxiety within 40 minutes. Again, 40 minutes is too early to involve gene transcription. What we are seeing is likely an immediate direct effect due to interruption of neuronal transmission and a prolongation of effect related to gene transcription leading to synaptogenesis.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Lars: Different doses, I'm not sure if that would work; they'd surely cause different degrees of short-term subjective effects, or even qualitatively different ones, so I don't know if it would address the nonspecific argument.

    Certainly would be a good way to answer other questions, though.

    Personally, in an MDMA trial, I would compare it to amphetamine. Same stimulant kick and euphoria but without the “empathogenic” features that make MDMA & friends unique.

  • http://www.blogger.com/profile/12987483359214068938 Will:Power

    Hi Zigs,

    http://www.ncbi.nlm.nih.gov/pubmed/20724638

    In that study the antidepressant effects were totally eliminated with mTOR inhibition by rapamycin, even when only injected into the PFC. Increased ERK and Akt phos was observed first at 0:30-1:30hrs, then increased synaptic proteins peaked at 1-6 hours and remained elevated up to 72hrs later. Tissue was collected 24hr after ketamine for synapse morphology analysis.

    The mTOR pathway controls translation initiation, i.e. mRNA to protein sythesis. I *think* it can induce protein synthesis extremely rapidly without the requirement for prior gene transcription. In this way rapid synaptogenesis is possible (note. not neurogenesis).

    http://genesdev.cshlp.org/content/15/7/807.full

    However another study I just remembered focused on an even earlier time point in the rapid antidepressant effects of NMDAR antagonists and implicated BDNF. This study found that resting NMDAR antagonism led to dis-inhibition of eEF2 and a rapid translational increase in BDNF. BDNF protein levels were markedly increased at 30mins whilst mRNA was not at 30min or 24hrs. An inhibitor of protein synthesis prevented antidepressant effects, whilst an inhibitor of gene transcription did not.

    This study also suggested that mTOR induction may maintain antidepressant response, potentially reconciling the previous mTOR findings. Notably eEF2 is also regulated via the mTOR-S6 pathway.

    http://www.ncbi.nlm.nih.gov/pubmed/21677641

    Notably all these effects are not achievable with current monoaminergics till after chronic administration.

  • http://www.blogger.com/profile/12987483359214068938 Will:Power

    I want to make it clear I'm not arguing against basic effects on neurotransmission and regional brain circuitry as being important to the mechanism of NMDAR antagonists. I'm just pointing to some interesting science as per the discussion. All these areas and system are likely involved.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    @Will:Power – Thanks. That is interesting!

  • Ivana Fulli MD

    neuroskeptic,

    You ask for proper clinical trials and all the elaborate interesting points raised by your commentators makes your demand more urgent and legitimate.

    You wrote: ” Ketamine may be cheap compared to ECT or a long course of treatment, but it's still an IV infusion over 40 minutes; it would be even cheaper if you could, say, give a sublingual benzo and get the same effect.”

    To my mind the first part of your sentence means that we need a proper trial comparing IV infusion of Ketamine with IV infusions of placebo and a benzodiazepine.

    Actually, years ago in Pr Ginestet psychiatric service( Hôpital Paul Brousse APHP France ) a client of mine I had confided to them in an emergency due to suicidal threats (in the course of a violent divorce procedure) received IV infusions of a benzodiazepine for several days on the idea that she was immature and needed the reassuring effect of IV.The woman was certainly discharged feeling a lot better and not talking anymore of taking her life and accepting her husband decision to divorce her.

  • Ivana Fulli MD

    I really can't see how you can escape comparing ketamine against pbo et other drugs administred by slow IV perfusion.To my mind a benzodiazepine in a pill will not do.

    But otherwise I think Neuroskeptic cannot be more right in asking for proper clinical trials.

    The more so since nice and clever commentators have positive anecdoctal experiences with ketamine on their clients.

    And it is about time that amphetamines have their honest and proper clinical trials to. Without forgetting hallucinogens and hormones.

    Thanks Neuroskeptic.

  • Ivana Fulli MD

    Zigs,

    What you wrote was very interesting for sure.

    To form my own “educated opinion ” about it I would need to know in which counbtry you work and how often you “offer” your client one hour of your time -when you are not offering ketamine treatment that is?

  • http://www.blogger.com/profile/14497597810278614165 Aykay101

    Hi Neuroskeptic. I've been thinking about the ketamine antidepressant issue for a while. Perhaps a way to eliminate the placebo effect would be to first give people a general anesthetic (the big question will be with what agent) and then while they are unconscious administer the dose of ketamine (or placebo). You could use perhaps iv midazolam at sufficient doses for the GA. This would have the added benefit of making the patients amnestic for the whole event. The problem is if midazolam itself, for instance, has specific antidepressants actions. Nevertheless, if some difference was observed between the two groups then a more specific claim could be made on ketamine's neurobiological effects. Also this could raise the question of whether been aware of the dissociative effects of the ketamine itself plays some role in response. Getting ethics to place people under GA will be difficult but all ECT trials have to do this anyway.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    @Ivana Fulli: I am a clinical fellow at an academic center in Canada. Patients are entirely covered by government health care. Considering that I work in a specialty clinic, I have a lot more time to spend with patients than the average community physician. When I see patient for usual care, I offer medication management and supportive psychotherapy (I am trained in CBT and psychodynamic and practice an integrative approach).

    There is obviously the question of whether there is an “enhanced placebo effect” aspect of spending more time with with patients when giving ketamine. However, from my experience (and supported by the literature), placebo response rates are much lower for severely ill and treatment refractory patients. You can spend an hour with them and you do not get much more benefit than giving them 20 minutes of quality time.

  • Ivana Fulli MD

    Zigs,

    Thanks for answering me. Canadian citizens seem to be priviledged with their mental health system.

    I hope you will publish your results.Even their psychoanalysts semm beter than ours!

  • Philotrophic

    Midazolam IV has powerful amnesic and sedative effects, comparable to ketamine. Its dissociative and amnesic effects are often utilized for out-patient procedures such as colonoscopies, where it is used interchangeably with ketamine, depending on what is available.

    Unfortunately I haven't used either myself, but the patient response seems similar clinically. 0,5mg/kg is also a low dose of ketamine, so I believe midazolam will be an effective placebo for blinding.

  • http://www.blogger.com/profile/15156271401086595761 Euan Briggs

    Why is it a problem that a drug produces a pronounced dramatically mind altering state?
    The root of this problem lies with the actions of people like Timothy Leary and Terence McKenna, who were responsible for turning promising psychiatric drugs into toys for hedonists, rather than useful tools.
    If someone takes a drug like MDMA with the attitude 'I want to get high', they will have a recreational experience. If instead they are primed before the experience to look upon it as a therapeutic opportunity to experience an 'outside view' of their 'normal' entrenched state of mind, the result can be an epiphany of self-insight and leave them with a truly constructive outcome.

    I do not advocate the chronic administration of such drugs as a treatment, but rather acute, single doses even. It is the opportunity to see yourself in a different light which really helps.

    This is what I find particularly interesting about NMDA receptor antagonists such as ketamine – the 'out of body' dissociative experience, can be interpreted by someone who has taken the drug as a chance to experience themselves in the third person, taking cognitive behavioural therapy to a new and very real level.

    Furthermore, ketamine itself is not necessarily the answer here. The substance (RS)2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone is an NMDA receptor antagonist which produces similar 'illusory body ownership' effects to ketamine but with less pronounced visual/auditory/psychedelic side effects.

    It is time for society to examine existing attitudes to drugs and do away with the taboos associated with research involving chemicals that have been abused as mere doorways to recreation.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Euan: Those are all good points. My point in this post was merely that we need to work out whether ketamine produces improvement through a therapeutic opportunity via mind-altering effects, as opposed to having 'direct' antidepressant effects.

    Either way, it's very interesting, but the clinical & scientific implications are totally different.

  • Ivana Fulli MD

    Neuroskeptic,

    I would be grateful if you could elaborate and explain what you mean by :

    “(…)via mind-altering effects, as opposed to having 'direct' antidepressant effects”

    The mind-altering effect of ketamine -which cannot easily be denied since it is used with surgery clients – could produce a marked placebo effect in itself (something is really happening to my brain). But I suspect you intended something different.

  • http://www.blogger.com/profile/15156271401086595761 Euan Briggs

    neuroskeptic said: “we need to work out whether ketamine produces improvement through a therapeutic opportunity via mind-altering effects, as opposed to having 'direct' antidepressant effects.”

    Since we know the mind-altering effect itself is not a placebo effect, is it really necessary to distinguish between this and a 'direct' anti-depressant effect, are the two mutually exclusive?

  • Ivana Fulli MD

    Euan,

    The mind altering effect of ketamine could act as a very strong “antidepressant placebo effect” enhancer since the client feels something really happening to his mind.

  • Anonymous

    I'm am a high functioning Bipolar patient with rapid cycling and refractory major depression.

    I have experienced both ECT and a Ketamine infusion. I have not had success with either – however the Ketamine infusion was only a one time event so not much of a data point.

    Being that ECT is highly intrusive and the memory loss experienced is significant, I would welcome more research into other potential solutions such as Ketamine.

    One of the big issues that I see is one of dosing. I have never been a drug user, but for some reason, I have an extremely high tolerance to medications. Prescribed diazepam, was as high as 80mgs a day (for several years) and I was still functioning (with a cocktail of other meds). During ECT they had to use 3 X the pain meds, and more Brevitol than would normally be indicated. Explanation by Dr. is that everyone reacts to/is effected by meds differently. So that brings up dosage.

    Unfortunately I am not aware of the dosing for my Ketamine trial, but I felt very little during the 40 minute procedure, with no recognizable effects afterwards. But what is the therapeutic dosage? How does one account for natural, individual tolerance? I think this is even a bigger issue in Bipolar patients since there are many drugs that have a different effect , or even a reverse effect, than what a 'normal' effect should be.

    Anyway from someone that appreciates all of your hard work, and whose life has been saved or extended, while suffering a myriad of side effects and setbacks,

    Thank you.

  • Anonymous

    “Also, they used to give amphetamine to treat depression (still do in very treatment resistant cases I believe)”

    I was surprised to see this addressed so late in the comments, and never in the main blog post. This is exactly why amphetamine would make a very poor active placebo– because it has accepted therapeutic value for depressed patients. It is not a placebo at all!

    It would be perfectly appropriate to not only test ketamine against placebo, but against current standard of care. However, amphetamine, while indicated for depression, is far from standard of care. Data comparing amphetamine to ketamine wouldn't be very useful to anyone.

    Organizing an experiment like this would be best served by a few protoexperiments to establish the best active placebo, as measured by participants' reports of which arm they believed themselves to be in. A sense of being high comes largely from non-drug factors; I wouldn't be surprised if patients administered oral niacin were completely unable to guess if they were in the treatment arm. (Although as has been mentioned, the best placebo would involve the same method of administration, ocurring over the same period of time.)

  • Anonymous

    I have been under various regiments of antidepressants over many years. My latest therapy is composed of 3 different antidepressants. They work but not to the level I wished. More than a year ago, I had the occasion to use Ketamine. At the following consultation with my “shrink”, I stated that my mood was so much improved for about 7 days after using “K”. I asked if he knew of an equivalent antidepressant based on Ketamine. I was not asking for something to get me high but rather a medication based on similar chemistry.

    I am really optimistic that “K” based antidepressant may be available in the near future.

    “K” really worked for me. It is no more something I do/take. I am only glad to know that what I felt could in fact be based on a real “side effect” of Ketamine

  • http://www.blogger.com/profile/03473599916182397588 Unknown

    my question is, are there any people out there who have had success with the .5mg ketamine injections, and who once the effects wore off, just continued gettting more injections. i realize the financial cost is generally outrageous, and this keeps most from being able to do this. but are there any out there with chronic major depression and/or anxiety, ptsd etc, who have regualrly had the injections for a year or more? and if so, has the ketamine (at the same dose, and at the same frequency of injection) maintained its efficacy? perhaps there's someone out there who either can financially afford this, or who has special circumstances allowing for regular injections, who could answer this? my example would be that say if ketamine injection works well for 10 days, but by day 11 it generally starts losing its effectiveness for someone, and so then the person uses this as their schedule of injection (.5mg injection every 10 days); does the drug tend to maintain its efficacy? or do people generally need higher doses or more frequent shots over time? or perhaps the opposite; as synapses form and neurons repair (and whatever else the apparrent NMDA antagonism /glutamate modulation etc does), perhaps people over time began to build sustainable lasting benefits from the ketamine, and can then began spacing out injections/titrating off until it's no longer needed? this would of course be the ideal. does anyone know of cases where the drug atleast maintains its efficacy over a year or longer with regular scheduled injections? i am told by a very reputable psychiatrist that this can very well be the case. and that it's only the cost, inconvenience, and potential discomfort (hallucinatory etc) of the injection administration that keeps this from being performed. he tells me that at this dosage and at no closer than 10 days between shots, there is NO reported lab abnormalities, bladder or kidney problems,,,and that the drug generally keeps its efficacy indefinitely (for those who it works for initially). is there anyone out there who could confirm this, or provide any info of known cases that supports this line of thinking? i already know that of course ketamine doesnt work for everyone, but for those who it does help……any data on above questions? any patients recieving regular longterm injections out there??

  • Anonymous

    Hi

    For those of you interested in Ketamine, it seems there is a company out there that has come up with a drug that uses the chemical process of ketamine but without the side effects. Unfortunately it looks like the IV won't be ready for 4 or so years and the oral tablet in about 6 years. Google 'Naurex'. Their first product is called GLYX-13

  • http://survivingantidepressants.org Altostrata

    I talked to a psychiatrist who did an investigation of ketamine in clinical practice. He said the effect was inconsistent and, where it could be called beneficial, temporary. Patients did not get positive effects from a second IV.

    Exactly the results you would expect from a street drug temporarily rehabilitated as a psychiatric treatment. Some people get high, others don't, the novelty wears off.

    The only group not represented were those prone to chronic recreational use. For that, see bluelight.ru or erowid.

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Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.

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